Figures and data
Overview of the experimental design.
(A). Participants were assigned to the counterconditioning (CC) or extinction (Ext) group. On day 1, participants performed two blocks of acquisition of category-conditioned threat responses separated by a 30 second break, followed by CC or extinction. Day 2 consisted of a spontaneous recovery test, a reinstatement procedure and test, an item memory test and a valence-specific response characterization. Valence and arousal ratings for the different categories were taken before or after the tasks as indicated by ‘V+A Rating’. All tasks were performed in an MRI scanner. (B) During acquisition, participants viewed trial-unique exemplars of objects and animals. Exemplars of one category (CS+ animals or objects counterbalanced) were paired with a shock in 50% of trials. CS- trials were not reinforced. (C) Participants in the CC group could earn a monetary reward if they responded quickly enough to exemplars in the CS+ category. (D) Participants in the Ext group underwent extinction. During the extinction task, recovery test and reinstatement test, neither CS+ nor CS- exemplars were paired with a shock. (E) In the valence-specific response characterization task, participants viewed three different coloured squares. One colour was associated with shock (CS+S), one colour with reward (CS+R) and one colour served as CS-. The trial structure was otherwise identical to the acquisition and CC tasks. (F) In all Pavlovian tasks, trial onset was marked by presentation of a unique category exemplar. After a variable interval, a ring appeared, to which participants were instructed to respond as quickly as possible. Upon response, the ring shifted in colour as response confirmation. In the acquisition task, shocks could occur 0.5-1.5-seconds after the response window had elapsed (indicated as ‘pre-shock). The category exemplar and cue remained visible 1 second after potential shock administration (indicated as ‘post-shock’). During CC, participants received visual feedback for 2 seconds (+€0.50 approximately the fastest 70% of trials, +€0.00 on other trials). During the other tasks, participants viewed neutral feedback (three dots). Trials were separated by an 8-10 s intertrial interval, during which a fixation cross is displayed in the centre of the screen.
Differential PDRs during CC/extinction and explicit ratings of arousal and valence provided after the counterconditioning or extinction phase.
(A) Differential PDRs for the early (light red) and late (dark red) phase of counterconditioning (CC, solid bars) or extinction (EXT, open bars). Participants undergoing CC showed increased differential PDRs as compared to participants undergoing extinction. (B) Arousal and (C) valence ratings displayed separately for participants assigned to the counterconditioning (CC, solid bars) and extinction (EXT, open bars) groups. Participants that had undergone CC gave stronger differential arousal scorings than participants that had undergone extinction. In addition, participants that underwent CC showed flipped differential valence ratings: while valence differential valence ratings were negative after extinction, the direction reversed to positive differential ratings after CC. Error bars represent ± standard error of the mean. *=p<0.05, **=p<0.01, ***=p<0.001, ≠ indicates that the bar is significantly different from 0.
Differential PDRs during the last two trials of extinction (grey) and the first two trials of the spontaneous recovery test (dark red).
Differential PDRs show selective spontaneous recovery after extinction (Ext group, open bars) but not after CC (CC group, solid bars). During the first two trials of the spontaneous recovery test, differential PDRs are increased in the Ext group as compared to the CC group. Insets show PDRs to the CS+ (red) and CS- (blue) during the last two trials of extinction and the first two trials of the spontaneous recovery test. While the Ext group shows differential responding during the spontaneous recovery test, the CC group does not. Error bars represent ± standard error of the mean. *=p<0.05, #=p<0.05 one-tailed significance.
Stimulus-type specific activation differs between participants undergoing CC versus extinction.
A. Whole-brain Group x CS-type interaction effects revealed distinct stimulus-specific activation of regions including the anterior cingulate, cuneus, nucleus accumbens, caudate, thalamus and inferior frontal gyrus during the counterconditioning vs. extinction phase. Panel A displays group F-images (see Table 1 for directions) FWE-corrected at p<0.05, cluster-forming threshold p=0.001. B. The right amygdala showed a Group x CS-type x Phase interaction during the CC/extinction task, indicating that CC compared to extinction is associated with decreased activation of the amygdala. C. The bilateral NAcc showed a Group x CS-type interaction during the CC/extinction task, revealing increased NAcc activation in response to the CS+ compared to the CS- in the CC but not in the Ext group. Panel B and C display group F-images FWE-SVC at p<0.05, cluster-forming threshold p=0.001, along with post-hoc tests on mean parameter estimates from the complete ROI included in the analyses. ** p<0.01, * p<0.05, ≠ indicates that the value is significantly different from 0.
Whole-brain main effects of group (CC, Ext), CS type (CS+, CS-) and phase (early, late) and interactions, during the counterconditioning/extinction task. Cluster-forming threshold p=0.001, FWE-corrected at p<0.05, clusters were labelled using the Talairach Daemon atlas and the AAL atlas for ROIs. For each cluster, the peak voxel coordinates (MNI space) and regions are reported, and additional regions contained within the cluster are added in italics. See Supplementary Table 1 for main effects of CS-type.
ROI analyses during the CC/extinction task reveal distinct activity in the hippocampus and left vmPFC.
During the CC/extinction task, stimulus-specific activation of the hippocampus (C) and left vmPFC (D) changes differently between groups. ** p<0.01, * p<0.05, ≠ indicates that the bar is significantly different from 0. Group F-images FWE-SVC at p<0.05, cluster-forming threshold p=0.001, along with post-hoc tests on mean parameter estimates from complete ROI included in the analyses.
Twenty-four hour recognition memory results.
During acquisition and extinction on the first day of the experiment, participants viewed trial-unique exemplars from two semantic categories (objects, animals) that served as CS+ and CS-. The next day, participants completed a surprise memory test for these items, mixed with an equal number of novel exemplars. Participants recognized relatively more items from the CS+ category, and participants that underwent CC showed improved item recognition compared to participants in the Ext group. Error bars represent ± standard error of the mean. *=p<0.05.
Pupil dilation responses (PDRs), explicit arousal and valence rating for the different CSs presented during the valence-specific response characterisation task.
(A) PDRs to the shock reinforced (CS+S), reward reinforced (CS+R) and CS- stimuli, averaged across the task and all participants. PDRs were increased for the CS+S and CS+R as compared to the CS- (B) Explicit ratings of arousal and (C) valence provided immediately after the task. Explicit ratings of arousal for the CS+S exceeded ratings for the CS-, and the CS+R was rated higher in arousal than the CS+S. Valence ratings (1=extremely negative, 10=extremely positive) for the CS+R were more positive than ratings for the CS-, while ratings for the CS+S were more negative than for the CS- and CS+R. Error bars represent ± standard error of the mean *=p<0.05, ***=p<0.001
Differential PDRs during acquisition and explicit ratings of arousal and valence provided after acquisition.
(A) Differential PDRs for the early (light red) and late (dark red) phase of the acquisition task, (B) arousal and (C) valence ratings, displayed separately for participants assigned to the counterconditioning (CC, solid bars) and extinction (EXT, open bars) groups. Both groups showed comparable differential PDRs and arousal ratings during the acquisition task. Participants in both groups showed negative differential valence ratings (stronger negative valence for CS+ vs. CS-), although this effect was stronger in the Ext group. Error bars represent ± standard error of the mean. *, p<0.05. ≠. Significantly different from 0
Differential threat responses during acquisition revealed CS-specific activation of clusters encompassing a range of regions including the bilateral insula, thalamus, precuneus, anterior cingulate and midbrain.
Group F-image of the effect of CS type, thresholded at cluster-level FWE-corrected p<0.05, cluster-forming threshold p=0.001, displayed on the single-subject high-resolution T1 volume provided by the Montreal Neurological Institute (MNI).
Whole-brain main effects of group (CC, Ext), CS type (CS+, CS-) and phase (early, late) and interactions, during the acquisition task.
Cluster-forming threshold p=0.001, FWE-corrected at p<0.05, clusters were labelled using the Talairach Deamon atlas and the AAL atlas for ROIs. For each cluster, the peak voxel coordinates (MNI space) and regions are reported, and additional regions contained within the cluster are added in italics.
Whole-brain main effect of CS-type during the CC/extinction task.
Cluster-forming threshold p=0.001, FWE-corrected at p<0.05, clusters were labelled using the Talairach Daemon atlas and the AAL atlas for ROIs. For each cluster, the peak voxel coordinates (MNI space) and regions are reported, and additional regions contained within the cluster are added in italics.
During the spontaneous recovery test, stimulus type-specific activation of the inferior temporal and frontal gyri differed between groups.
The inferior temporal Gyrus (A) and Inferior frontal gyrus (B) show increased CS+-specific activation in the CC group as compared to the Ext group. Group F-images thresholded at FWE-corrected p<0.05, cluster-forming threshold p=0.001, displayed on the single-subject high-resolution T1 volume provided by the Montreal Neurological Institute (MNI) and parameters estimates from peak voxels.
Peak voxel coordinates and statistics of activations during the spontaneous recovery phase in the CC group.
Clusters were labelled using the AAL atlas. For each cluster, the peak voxel coordinates and regions are reported, and additional regions contained within the cluster are added in italics. Clusters are whole-brain FWE-corrected at p<0.05.
